Immune-related adverse events are a frequently observed consequence of immunostimulatory antibody therapy. These immune-related adverse events, which can be severe, and even life-threatening, include autoimmune responses, such as diarrhea, enterocolitis, dermatitis, hypophysitis, panhypopituitarism, rash, pruritis, and vitiligo (see, e.g., U.S. Patent Publication No. 2004/0241169 A1).
Anti-CTLA-4 antibodies are known immunostimulatory agents (see, e.g., PCT Publication Nos. WO 01/14424 and WO 00/37504, which describe human sequence anti-human CTLA-4 antibodies). Non-human CTLA-4 antibodies have been used in the various studies. U.S. Pat. No. 5,855,887 discloses a method of increasing the response of a mammalian T cell to antigenic stimulation by combining a T cell with a CTLA-4 blocking agent. U.S. Pat. No. 5,811,097 discloses a method of decreasing the growth of non-T cell tumors by administering a CTLA-4 blocking agent. U.S. patent application Ser. Nos. 09/644,668 and 09/948,939 disclose human CTLA-4 antibodies. Each of these patents and applications is hereby incorporated by reference.
Therapy with an immunostimulatory agent, such as an anti-CTLA-4 antibody, is associated with certain adverse events, which appear to be mediated by the immune system. For example, adverse events related to MDX-010 (see PCT Publication No. WO 01/1424) therapy appear to have an immune etiology and may be a consequence of the intrinsic biological activity of MDX-010. These adverse events may be due to a loss of tolerance to some self-antigens or an exaggerated reaction to foreign antigens (e.g., gut bacteria). Although skin adverse events are most common, the most clinically significant immune-related adverse event following MDX-010 therapy is diarrhea secondary to enterocolitis. The enterocolitis observed following MDX-010 therapy is grossly (e.g., endoscopically) and histologically similar to inflammatory bowel disease. The gross and microscopic characteristics of ulcerative colitis and Crohn's disease are well-known. See, e.g., Harrison's Principles of Internal Medicine (15th ed. 2001) pp. 1681-1685. In most cases, this immune-related enterocolitis resolves with symptomatic treatment including intravenous hydration and high-dose parenteral steroids. In certain cases, however, the enterocolitis associated with immunostimulatory therapeutic antibody induced enterocolitis is refractory to steroid therapy.
Interestingly, in one study, almost 45% of patients developing an autoimmune-like adverse event also experienced a clinical response, including a patient with hypopituitarism, who demonstrated a durable complete response. These adverse events, likely reflect a loss of tolerance to some self antigens, or a hyper-response to bacterial antigens present in the gut or skin, and are therefore mechanism-related and may be directly linked to the clinical antitumor activity of MDX-010.
Accordingly, it would be desirable to provide methods for effective treatment of adverse events, which can accompany immunostimulatory therapeutic antibody, e.g., anti-CTLA-4 antibody, treatment of a disease or condition. In particular, a need exists for treatment of immune-related enterocolitis following immunostimulatory therapeutic antibody treatment, which does not interfere with the desired immune enhancement (e.g., anti-tumor immunity).